التفاصيل البيبلوغرافية
| العنوان: |
Constitutively active ESR1 mutations in gynecologic malignancies and clinical response to estrogen-receptor directed therapies. |
| المؤلفون: |
Gaillard, Stéphanie L.1 (AUTHOR) stephanie.gaillard@jhmi.edu, Andreano, Kaitlyn J.1 (AUTHOR), Gay, Laurie M.1 (AUTHOR), Steiner, Meghan1 (AUTHOR), Jorgensen, Matthew S.1 (AUTHOR), Davidson, Brittany Anne1 (AUTHOR), Havrilesky, Laura J.1 (AUTHOR), Alvarez Secord, Angeles1 (AUTHOR), Valea, Fidel A.1 (AUTHOR), Colon-Otero, Gerardo1 (AUTHOR), Zajchowski, Deborah A.1 (AUTHOR), Chang, Ching-Yi1 (AUTHOR), McDonnell, Donald P.1 (AUTHOR), Berchuck, Andrew1 (AUTHOR), Elvin, Julia A.1 (AUTHOR) |
| المصدر: |
Gynecologic Oncology. Jul2019, Vol. 154 Issue 1, p199-206. 8p. |
| مصطلحات موضوعية: |
*GYNECOLOGIC cancer, *HORMONE therapy, *THERAPEUTICS, *ESTROGEN receptors, *AROMATASE inhibitors, *FALLOPIAN tubes |
| مستخلص: |
Endocrine therapy is often considered as a treatment for hormone-responsive gynecologic malignancies. In breast cancer, activating mutations in the estrogen receptor (mutESR1) contribute to therapeutic resistance to endocrine therapy, especially aromatase inhibitors (AIs). The purpose of this study was to evaluate the frequency and clinical relevance of ESR1 genomic alterations in gynecologic malignancies. DNA from FFPE tumor tissue obtained during routine clinical care for 9645 gynecologic malignancies (ovary, fallopian tube, uterus, cervix, vagina, vulvar, and placenta) was analyzed for all classes of genomic alterations (base substitutions (muts), insertions, deletions, rearrangements, and amplifications) in ESR1 by hybrid capture next generation sequencing. A subset of alterations was characterized in laboratory-based transcription assays for response to endocrine therapies. A total of 295 ESR1 genomic alterations were identified in 285 (3.0%) cases. mutESR1 were present in 86 (0.9%) cases and were more common in uterine compared to other cancers (2.0% vs <1%, respectively p < 0.001). mutESR1 were enriched in carcinomas with endometrioid versus serous histology (4.4% vs 0.2% respectively, p < 0.0001 in uterine and 3.5% vs 0.3% respectively, p = 0.0004 in ovarian carcinomas). In three of four patients with serial sampling, mutESR1 emerged under the selective pressure of AI therapy. Despite decreased potency of estrogen receptor (ER) antagonists in transcriptional assays, clinical benefit was observed following treatment with selective ER-targeted therapy, in one case lasting >48 months. While the prevalence of ESR1 mutations in gynecologic malignancies is low, there are significant clinical implications useful in guiding therapeutic approaches for these cancers. • ESR1 mutations lead to constitutive activation of ERα and resistance to aromatase inhibitors. • A subset of gynecologic malignancies, particularly those with endometrioid histology, harbor ESR1 mutations. • ESR1 mutations may arise in the setting of treatment with AIs, or may be present in the initial tumor. • SERM/SERD therapy has the potential to provide benefit despite the presence of an ESR1 mutation. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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